Stype 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof

ABSTRACT

A process for preparing S type 2-substituted hydroxy-2-indolidinylbutyric ester compound [II]:  
                 
 
     wherein R o  is residue of nitrogen-containing fused heterocyclic carboxylic acid having absolute configuration of “R” (in which the nitrogen atom is protected), R1 and R2 are lower alkyl groups, and E is ester residue, which is useful as an intermediate for preparing camptothecin derivatives having antitumor activities, which comprises 2-ethylating 2-substituted hydroxy-2-indolidinylacetic ester compound [I]:  
                 
 
     wherein the symbols are as defined above.

FIELD OF INVENTION

[0001] This invention relates to an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound and a process for thepreparation thereof. More particularly, it relates to an S type2-substituted hydroxy-2-indolidinylbutyric ester compound which isuseful as an intermediate for preparing camptothecin derivatives havingantitumor activities and a process for preparing said compound in highyield and in high stereoselectivity.

PRIOR ART

[0002] There is known a process for preparing camptothecin derivativeshaving antitumor activities by Friedlaender reaction (cf. EP-A-540099,EP-A-296597, JP-A-6-87746, WO 90/03169, EP-A-418099), wherein it hasbeen investigated to find processes for preparing S type4-hydroxypyranoindolidine compounds of the formula [VIII] which areimportant as an intermediate:

[0003] Besides, it is reported, for example, in EP-A-220601 that an Stype 2-[(R)-N-tosyl-prolyloxy]-2-indolidinylbutyric ester compound ofthe formula [XXI]:

[0004] may be prepared by brominating at 2-position of a2-indolidinylacetic ester compound of the formula [XX]:

[0005] and reacting the resultant with an (R)-N-tosylproline and furtherethylating at 2-position of the reaction product, and further that acamptothecin derivative is prepared from said compound via an S type4-hydroxypyranoindolidine compound [VIII].

[0006] However, according to this process, the desired S type2-[(R)-N-tosylprolyloxy]-2-indolidinylbutyric ester compound [XXI] ismerely obtained in an amount of 2.6-4.6 times larger (44-64% d.e.) thanthat of a diastereomer having an absolute configuration of “R” at2-position which is simultaneously prepared, and the S type compound isisolated therefrom in a further lower yield, only 56%, by a fractionalrecrystallization [cf. Organic Synthetic Chemistry, vol. 49, No. 11, pp.1013-1020, 1991].

BRIEF SUMMARY OF THE INVENTION

[0007] This invention provides an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound useful as an intermediatefor preparing camptothecin derivatives in a high yield and in a highstereoselectivity,

DETAILED DESCRIPTION OF THE INVENTION

[0008] According to this invention, the desired S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound of the formula [II]:

[0009] can be prepared by reacting a 2-halo-2-indolidinylacetic estercompound of the formula [III]:

[0010] wherein X is a halogen atom, R¹ and R² are a lower alkyl group,and E is an ester residue, with an R type nitrogen-containing fusedheterocyclic carboxylic acid compound of the formula [IV]:

R^(o)OH  [IV]

[0011] wherein R^(o) is a residue of a nitrogen-containing fusedheterocyclic carboxylic acid having an absolute configuration of “R”which is obtained by removing hydroxy group from the carboxyl group ofsaid carboxylic acid compound (in which the nitrogen atom contained inthe residue is protected) or a salt thereof to give a 2-substitutedhydroxy-2-indolidinylacetic ester compound of the formula [I]:

[0012] wherein the symbols are as defined above, and then ethylating2-position of the resultant compound [I].

[0013] The process of this invention is characteristic in that the2-substituted hydroxy-2-indolidinylacetic ester compound [I] issterically bulky at the acetal moiety and has a sterically bulkysubstituent containing an optically active nitrogen-containing fusedheterocyclic ring at 2-position thereof and hence it is ethylated withhigh yield and high stereoselectivity at 2-position, and thereby thedesired S type 2-substituted hydroxy-2-indolidinylbutyric ester compound[II] is obtained in a high selectivity such as 9 times or more higher(80% d.e. or more) than the diastereomer having an absoluteconfiguration of “R” at 2-position. Particularly, when the group “Y” inthe substituent R^(o) in the compound [I] is a 4-nitrophenylsulfonylgroup or a 4-biphenyl sulfonyl group, the desired compound is obtainedin much higher stereoselectivity of 20 times (90% d.e.) or 15.2 times(88% d.e.) higher, respectively and in much higher isolation yield of75% or 76%, respectively.

[0014] The R type nitrogen-containing fused heterocyclic carboxylic acidcompound [IV] in this invention means a compound having a carboxyl groupbound to a nitrogen-containing fused heterocyclic ring (the nitrogenatom contained in said compound is protected), and the carbon atom boundwith the carboxyl group has an absolute configuration of “R”, and thenitrogen-containing fused heterocyclic ring includes a benzene-fusednitrogen-containing heterocyclic ring, for example, atetrahydroisoquinoline ring, a tetrahydroquinoline ring, adihydroquinoline ring, or an indoline ring.

[0015] Suitable example of the nitrogen-containing fused heterocycliccarboxylic acid compound having an absolute configuration of “R” is acompound of the formula [XIX]:

[0016] wherein n is 0 or 1, and Y is a substituted or unsubstitutedarylsulfonyl group or a lower alkylsulfonyl group.

[0017] The above compound [XIX] wherein n is 1 means anN-substituted-1,2,3,4-tetrahydro-3-ylquinolinecarboxylic acid, and thecompound [XIX] wherein n is 0 means an N-substituted2-indolinecarboxylic acid. The substituent “Y” on the nitrogen atom ofthe above compound [XIX] includes a phenylsulfonyl, naphthylsulfonyl orbiphenylylsulfonyl group (which may optionally be substituted by amember selected from a nitro group, a lower alkyl group, a lower alkoxygroup, a cycloalkyl group, a halogen atom, or a thienyl group), or alower alkylsulfonyl group, for example, a phenylsulfonyl group, a tosylgroup, a 2,4,6-trimethylphenylsulfonyl group, a 4-nitrophenylsulfonylgroup, a 4-chlorophenylsulfonyl group, a 4-methoxyphenylsulfonyl group,a 4-cyclohexylphenylsulfonyl group, a 4-(3-thienyl)phenylsulfonyl group,a 2-naphthylsulfonyl group, a 4-biphenylylsulfonyl group, amethylsulfonyl group, and an ethylsulfonyl group.

[0018] Among the above, preferred compounds are a compound [XIX] whereinthe substituent “Y” on the nitrogen atom is a tosyl group, a2-naphthylsulfonyl group, a 2,4,6-trimethylphenylsulfonyl group, a4-biphenylylsulfonyl group, or a 4-nitrophenylsulfonyl group and n is 1,and a compound [XIX] wherein the substituent “Y” on the nitrogen atom isa tosyl group and n is 0. Particularly preferred compounds are acompound [XIX] wherein the substituent “Y” on the nitrogen atom is a4-biphenylylsulfonyl group or a 4-nitrophenylsulfonyl group and n is 1.

[0019] The R¹ and R² are a lower alkyl group, such as a methyl group, anethyl group, a propyl group, an isopropyl group, an n-butyl group, anisobutyl group; X is a halogen atom such as chlorine, bromine, iodine.The E includes any conventional ester residues, for example lower alkylgroups such as a methyl group, an ethyl group, a propyl group, anisopropyl group, an n-butyl group, or an isobutyl group. Among them,preferable groups are R¹ and R² being a methyl group, X being a chlorineatom or a bromine atom, and E being a methyl group or an ethyl group.

[0020] The reaction of the 2-halo-2-indolidinylacetic ester compound[III] and the R type nitrogen-containing fused heterocyclic carboxylicacid compound [IV] or a salt thereof is carried out in a suitablesolvent.

[0021] The salt of the R-type nitrogen-containing fused heterocycliccarboxylic acid compound [IV] includes an alkali metal salt (e.g.potassium salt, sodium salt), an alkaline earth metal salt (e.g.magnesium salt, calcium salt).

[0022] The reaction of the 2-halo-2-indolidinylacetic ester compound[III] and the R type nitrogen-containing fused heterocyclic carboxylicacid compound [IV] or a salt thereof is preferably carried out in thepresence or absence of an acid scavenger. Suitable examples of the acidscavenger are inorganic bases, such as an alkali metal hydride (e.g.lithium hydride, sodium hydride, potassium hydride), an alkali metalamide (e.g. lithium amide, sodium amide, potassium amide), an alkalimetal carbonate (e.g. sodium carbonate, potassium carbonate), an alkalimetal hydrogen carbonate (e.g. sodium hydrogen carbonate, potassiumhydrogen carbonate), an alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, lithium hydroxide), and organic bases, such as analkali metal alkoxide (e.g. sodium ethoxide, potassium tertbutoxide), analkali metal alkylamide (e.g. lithium diisopropylamide), a trialkylamine(e.g. triethylamine, trimethylamine), an N,N-dialkylaniline (e.g.N,N-dimethylaniline), 1,8-diazabicyclo [5.4.0]undeca-7-ene.

[0023] The solvent used in the reaction includes any conventionalsolvent which does not affect on the reaction, and suitable examples arean amide type solvent (e.g. dimethylformamide, dimethylacetamide), anether solvent (e.g. tetrahydrofuran, dimethyl ether, dioxane), Thereaction is usually carried out at a temperature of from 20 to 100° C.,preferably from 50 to 70° C.

[0024] The subsequent 2-ethylation of the 2-substitutedhydroxy-2-indolidinylacetic ester compound [I] is carried out in asuitable solvent in the presence of an acid scavenger.

[0025] The ethylating agent is preferably an ethyl halide (e.g. ethyliodide, ethyl bromide), more preferably ethyl iodide. The acid scavengeris the same agents as mentioned above for the reaction of the2-halo-2-indolidinylacetic ester compound [III] and the R typenitrogen-containing fused heterocyclic carboxylic acid compound [IV] ora salt thereof, and particularly preferable agent is sodium hydride.

[0026] The solvent used in the reaction includes any conventionalsolvent which does not affect on the reaction, and suitable examples arean amide type solvent (e.g. dimethylformamide, dimethylacetamide), asulfoxide solvent (e.g. dimethylsulfoxide), an ether solvent (e.g.tetrahydrofuran, dioxane, dimethyl ether), an aromatic hydrocarbonsolvent (e.g. toluene, xylene, benzene, chlorobenzene), or a mixturethereof, and particularly preferable solvent is a mixture ofdimethylacetamide and toluene. The reaction is usually carried out at atemperature of from −10 to 50° C., particularly preferably at a roomtemperature. The desired compound [II] in a crude form thus obtained caneasily be purified by recrystallization to give a highly purifiedcompound [II].

[0027] The S type 2-substituted hydroxy-2-indolidinylbutyric estercompound [II] thus obtained is subjected to a catalytic reduction toreduce the cyano group thereof and then subjected to alkanoylation togive an S type 2-substituted hydroxy-2-(6-substitutedaminomethylindolidinyl)butyric ester compound of the formula [V]:

[0028] wherein R³ is a lower alkanoyl group, and other symbols arc asdefined above, and the resultant is subjected to nitrosation reactionand rearrangement to give an S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compoundof the formula [VI]:

[0029] wherein the symbols are as defined above. The compound [VI] isthen subjected to an intramolecular cyclization reaction, and thereafteror at the same time as the cyclization reaction, the acetal groupthereof is converted into a ketone group to give an S type 4-substitutedhydroxypyranoindolidine compound of the formula [VII]:

[0030] wherein the symbol is as defined above.

[0031] The above compound [VII] is subjected to Friedlaeader reactiontogether with an o-acylaniline compound of the formula [XIV]:

[0032] wherein the groups R⁵-R⁹ are each a hydrogen atom or asubstituent being optionally protected, in a conventional manner to givea camptothecin compound having a substituent on the 20-hydroxy group ofthe formula [XV]:

[0033] wherein the symbols are as defined above, and the compound [XV]is subjected to removal of R^(o) group and further, when the groupsR⁵-R⁹ are protected, subjected to removal of the protecting group, andfurther optionally to conversion into a salt thereof to give acamptothecin compound of the formula [XVI]:

[0034] wherein the groups R⁵¹-R⁹¹ are each a hydrogen atom or anunprotected substituent, or a salt thereof.

[0035] Besides, it is assumed that in the above intramolecularcyclization reaction of the S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compound[VI], there is produced a compound of the following formula:

[0036] wherein the symbols are as defined above.

[0037] The camptothecin compound [XVI] or a salt thereof may also beprepared by a process comprising the following steps:

[0038] (a-1) subjecting the S type 4-substituted hydroxypyranoindolidinecompound [VII] to removal of the group R^(o), or

[0039] (a-2) subjecting the S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compound[VI] to an ester hydrolysis to give an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound of theformula [IX]:

[0040] wherein the symbols are as defined above, subjecting the compound[IX] to an intramolecular cyclization reaction and thereafter orsimultaneously with the cyclization reaction converting the acetal groupthereof into a ketone group, and further optionally converting theproduct into a salt thereof to give an S type 4-hydroxypyranoindolidinecompound of the formula [VIII]:

[0041] or a salt thereof,

[0042] (b) subjecting the compound [VIII] to Friedlaender reactiontogether with an o-acylaniline compound [XIV] in a usual manner to givea camptothecin compound of the formula [XVII]:

[0043] wherein the symbols are as defined above,

[0044] (c) subjecting the compound [XVII] to removal of the protectinggroup of the groups R⁵-R⁹, when these groups contain a protecting group,and further

[0045] (d) optionally converting the product into a salt thereof.

[0046] Alternatively, the camptothecin compound [XVI] or a salt thereofmay be prepared by a process comprising the following steps:

[0047] (i) subjecting the S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound [VI] to an esterhydrolysis to give an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound [IX] or asalt thereof,

[0048] (ii) subjecting the compound [IX] to an intramolecularcyclization reaction and further optionally converting the product intoa salt thereof to give an S type 4-hydroxypyranoindolidine compound ofthe formula [X]:

[0049] wherein the symbols are as defined above, or a salt thereof,

[0050] (iii) reacting the compound [X] with a lower alkanoic acid of theformula [XI]:

R⁴OH  [XI]

[0051] wherein R⁴ is a lower alkanoyl group, or a reactive derivativethereof to give an S type 4-alkanoyloxypyranoindolidine compound of theformula [XII]:

[0052] wherein the symbols are as defined above,

[0053] (iv) converting the acetal group of said compound [XII] into aketone group to give an S type 4-alkanoyloxypyranoindolidine compound ofthe formula [XIII]:

[0054] wherein the symbols are as defined above,

[0055] (v) subjecting the compound [XIII] to Friedlaender reactiontogether with an o-acylaniline compound [XIV] in a usual manner to givea camptothecin compound having a substituent on the 20-hydroxy group ofthe formula [VIII]:

[0056] wherein the symbols are as defined above,

[0057] (vi) subjecting the compound [XVIII] to removal of the group R⁴and further to removal of the protecting group of the groups R⁵-R⁹, whenthese groups contain a protecting group, and further

[0058] (vii) optionally converting the product into a salt thereof.

[0059] In the above compounds, the groups R⁵-R⁹ include any substituentslike in known camptothecin derivatives (cf. for example, EP-A-540099,EP-A-296597, JP-A6-228141, WO 90/03169, EP-A-118099) is well as in thecamptothecin derivatives as disclosed in European Patent PublicationNos. 757049 and 781781, for example, the following groups:

[0060] (a) the adjacent two groups among the R⁵-R⁹ combine to form astraight chain or branched chain alkylene group having 2 to 6 carbonatoms, or are both a hydrogen atom, and one of the remaining groups is—Q_(q)—Alk_(p)—R¹⁰, and other two of the remaining groups are a hydrogenatom, a substituted or unsubstituted lower alkyl group, or a halogenatom,

[0061] (b) the adjacent two groups among the R⁵-R⁹ combine to form astraight chain or branched chain alkylene group having 2 to 6 carbonatoms, and any one carbon atom in the alkylene group is substituted by agroup of the formula: —Q_(q)—Alk_(p)—R¹⁰, and the remaining three groupsof the R⁵-R⁹ are a hydrogen atom, a substituted or unsubstituted loweralkyl group, or a halogen atom,

[0062] in the above (a) and (b), one or two methylene groups in thealkylene group may be replaced by —O—, —S— or —NH—,

[0063] Q is —O— or —NH—,

[0064] Alk is a straight chain or branched chain alkylene group having 1to 6 carbon atoms, which may optionally be intervened by an oxygen atom,

[0065] R¹⁰ is a protected amino group, a protected lower alkylaminogroup, a protected piperazino group, or a protected hydroxy group,

[0066] p and q are both 0 or 1, or when p is 1, q is 0.

[0067] The R⁵¹-R⁹¹ are a group derived from R⁵-R⁹ by removing theprotecting group, specifically the groups as defined for R⁵-R⁹ whereinthe group R¹⁰ is a group obtained by removing the protecting group, thatis, the group R¹⁰ being an amino group, a lower alkylamino group, apiperazino group, or a hydroxy group.

[0068] Preferred combinations of the groups R⁵¹-R⁹¹ are as follows:

[0069] (i) R⁷¹ is 3-aminopropyloxy, R⁵¹ is ethyl, and R⁶¹, R⁸¹ and R⁹¹are each hydrogen atom,

[0070] (ii) R⁵¹ is piperazinomethyl, R⁶¹ and R⁹¹ are each hydrogen atom,and R⁷¹ and R⁸¹ combine to form ethylenedioxy,

[0071] (iii) R⁵¹ is aminomethyl, R⁷¹ and R⁸¹ combine to formethylenedioxy, and R⁶¹ and R⁹¹ are each hydrogen atom,

[0072] (iv) R⁵¹ is aminomethyl, R⁷¹ and R⁸¹ combine to formmethylenedioxy, and R⁶¹ and R⁹¹ are each hydrogen atom,

[0073] (v) R⁶¹ is amino, and R⁵¹, R⁷¹, R⁸¹ and R⁹¹ are each hydrogenatom,

[0074] (vi) R⁵¹ and R⁶¹ combine to form amino-substituted trimethylene,R⁷¹ is methyl, R⁸¹ is fluorine atom, and R⁹¹ is hydrogen atom,

[0075] (vii) R⁵¹ and R⁶¹ combine to form trimethylene, R⁷¹ is3-aminopropyloxy, R⁸¹ and R⁹¹ are each hydrogen atom,

[0076] (viii) R⁷¹ is 3-aminopropyloxy, and R⁵¹, R⁶¹, R⁸¹ and R⁹¹ areeach hydrogen atom.

[0077] The salt of the S type 4-hydroxypyranoindolidine compound [VIII],S type 2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound[IX] or S type 4-hydroxypyranoindolidine compound [X] includes an alkalimetal salt (e.g. sodium salt, lithium salt), and the salt of thecamptothecin compound [XVI] includes a salt with an inorganic acid (e.g.hydrochloride, sulfate) or a salt with an organic acid (e.g. oxalate,tosylate).

[0078] In the above process for the preparation of a camptothecincompound, the reduction and alkanoylation of the S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound [II] arc carried out in asuitable solvent. The reduction is usually carried out by using acatalyst (e.g. Raney nickel) under hydrogen atmosphere at a roomtemperature to 60° C. The alkanoylation is usually carried out by usinga conventional alkanoylating agent (e.g. a lower alkanoic acid, a loweralkanoic halide, a lower alkanoic acid anhydride) at a room temperatureto 60° C. The solvent to be used in these reactions includes a loweralkanoic acid anhydride (e.g. acetic anhydride), a lower alkanoic acid(e.g. acetic acid), or a mixture of them. When a lower alkanoic acidanhydride, a lower alkanoic acid, or a mixture of them is used in thereduction reaction, they may be used also as an alkanoylating agent, andin such a case, the reduction and the alkanoylation can proceed in asingle step.

[0079] The nitrosation and rearrangement of an S type 2-substitutedhydroxy-2-(6-substituted aminomethylindolidinyl)butyric ester compound[V] can be earned out by a similar method to that disclosed in Journalof Medicinal Chemistry, vol. 23, pp. 554-560 (1980) in a suitablesolvent. The nitrosation is carried out under an acidic condition with aconventional nitrosating agent (e.g. sodium nitrite, potassium nitrite)at 0C. The solvent to be used in this reaction includes a lower alkanoicacid anhydride (e.g. acetic anhydride), a lower alkanoic acid (e.g.acetic acid), or a mixture of them.

[0080] The subsequent rearrangement reaction can be carried out byheating the product obtained by the above nitrosation at a temperatureof 60 to 70° C. The solvent to be used in the rearrangement reactionincludes a halogenated hydrocarbon (e.g. carbon tetrachloride,chloroform, methylene chloride), an ester solvent (e.g. ethyl acetate),a non-aromatic hydrocarbon solvent (e.g. n-hexane), an aromatichydrocarbon solvent (e.g. toluene).

[0081] The ester hydrolysis of the S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compound[VI] can be carried out by a conventional method for the esterhydrolysis in a suitable solvent in the presence of a base.

[0082] The base to be used in the ester hydrolysis includes inorganicbases, such as an alkali metal hydroxide (lithium hydroxide, sodiumhydroxide, potassium hydroxide), an alkaline earth metal hydroxide (e.g.calcium hydroxide), an ammonium hydroxide, an alkali metal carbonate(e.g. sodium carbonate, potassium carbonate), an alkali metal hydrogencarbonate (e.g. sodium hydrogen carbonate), organic bases, such as analkali metal alkoxide (e.g. sodium ethoxide, sodium methoxide), analkali metal phenoxide (e.g. sodium phenoxide), a mono-, di- ortri-lower alkylamine (e.g. methylamine, ethylamine,N,N-dimethyl-1,3-propanediamine, trimethylamine, triethylamine). Thesolvent includes an alcohol solvent (e.g. methanol, ethanol, propanol,isopropanol, butanol), a sulfoxide solvent (e.g. dimethylsulfoxide), ahalogenated hydrocarbon solvent (e.g. methylene chloride), an ethersolvent (e.g. tetrahydrofuran), or a mixture of the organic solvent withwater. When the base is a liquid, it may be used also as a solvent. Thereaction is preferably carried out at a temperature of 0 to 50° C., morepreferably at a room temperature.

[0083] When the intramolecular cyclization reaction of an S type2-substituted hydroxy-2-(6-substituted hydroxymethylindolydinyl)butyricester compound [VI] or an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound [IX] or asalt thereof and the conversion of the acetal group into a ketone groupare carried out simultaneously, they can be carried out in a single stepby treating the compound with a suitable acid. The acid includes aninorganic acid (e.g. hydrochloric acid, sulfuric acid), an organic acid(e.g. trifluoroacetic acid), and a mixture of them with water. The acidmay be used also as a solvent.

[0084] On the other hand, when the intramolecular cyclization reactionof an S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolydinyl)butyric ester compound [VI] or an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound [IX] or asalt thereof is first carried out and thereafter the conversion of theacetal group into a ketone group is carried out, the reactions can becarried out by treating the compound with an acid (e.g. acetic acid,citric acid) weaker than the acid used in the above single step reactionand then treating the resultant with the same stronger acid as used inthe above single step reaction. For example, when the S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound [IX] or asalt thereof is treated with a weaker acid, there is obtained an S type4-hydroxypyranoindolidine compound [X], which is converted into an Stype 4-hydroxypyranoindolidine compound [VIII] by treating it with astronger acid.

[0085] The reaction of an S type 4-hydroxypyranoindolidine compound [X]or a salt thereof with a lower alkanoic acid [XI] or a reactivederivative thereof can be carried out in the presence of a base.

[0086] The lower alkanoic acid [XI] includes, for example, acetic acid,and the reactive derivative thereof includes an acid anhydride (e.g.acetic anhydride), an acid halide (e.g. acetic chloride), an activatedester (e.g. p-nitrophenyl ester). The base includes an alkali metalhydride (e.g. sodium hydride, potassium hydride), an alkali metalcarbonate (e.g. sodium carbonate, potassium carbonate), an alkali metalhydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogencarbonate), pyridine, and 4-N,N-dimethylaminopyridine. The reaction isusually carried out at a temperature of 0 to 50° C., preferably at aroom temperature.

[0087] The subsequent conversion of the acetal group of an S type4-substituted hydroxypyranoindolidine compound [XII] into a ketone groupcan be carried out by treating the compound with a suitable acid. Theacid may be the same acid as used in case of carrying out theintramolecular cyclization reaction of an S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric acid compound[VI] or an S type 2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acidcompound [IX] or a salt thereof and the conversion of the acetal groupinto a ketone group in a single step.

[0088] The reaction of an S type 4-substituted hydroxypyranoindolidinecompound [VII], an S type 4-hydroxypyranoindolidine compound [VIII] or asalt thereof, or an S type 4-substituted hydroxypyranoindolidinecompound [XIII] with an o-acylaniline compound [XIV] can be carried outby the known Friedlaender reaction [cf. Organic Reactions, vol. 28, pp.37-202, John Wiley & Sons, Inc., New York (1982)].

[0089] The 4-substituted hydroxypyranoindolidine compound [VII] and4-alkanoyloxypyranoindolidine compound [XIII] are more stable than an Stype 4-hydroxypyranoindolidine compound [VIII] or a salt thereof andfurther are less affect on decomposition of o-acrylaniline compound[XIV] during the Friedlaender reaction and thereby can reduce theundesirable by-production of contaminating impurities, and hence, thosecompounds are favorably used in the reaction with less amount of theo-acylaniline compound [XIV], with simple post-reaction treatment suchas purification and can give the desired camptothecin compounds [XVI] ora salt thereof in a higher yield.

[0090] Moreover, the 4-alkanoyloxypyranoindolidine compound [XIII] has amolecular weight much smaller than that of the 4-substitutedhydroxypyranoindolidine compound [VII], and hence, it can be used in theFriedlaender reaction in a smaller amount with a smaller reactionvessel.

[0091] The removal of the protecting groups contained in the groupsR⁵-R⁹ can be carried out by a conventional method suitable to theprotecting groups contained therein. For example, when the aminoprotecting group is a benzyloxycarbonyl group, it can be removed bycatalytic reduction in the presence of palladium-carbon in a suitablesolvent (e.g. tetrahydrofuran, methanol), and when the amino protectinggroup is a tert-butoxycarbonyl group, it can be removed by treating itwith an acid (e.g. hydrochloric acid, trifluoroacetic acid) in asuitable solvent (e.g. tetrahydrofuran, methanol, dioxane, methylenechloride).

[0092] The removal of the residue R^(o) from an S type 4-substitutedhydroxypyranoindolidine compound [VII] or from a camptothecin compoundhaving 20-substituted hydroxy group [XV] can be carried out by aconventional ester hydrolysis in the presence of a base in a suitablesolvent. The base and solvent are the same as those used in the esterhydrolysis of an S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound [VI]. The reaction maybe carried out under cooling, at a room temperature, or with heating.

[0093] Besides, the removal of the group R⁴ from the camptothecincompound having 20-alkanoylated hydroxy group [XVIII] can be carried outin the same manner as in the ester hydrolysis of an S type 2-substitutedhydroxy-2-(6-substituted hydroxymethylindolidinyl)butyric ester compound[VI] or in the removal of the residue R^(o) from an S type 4-substitutedhydroxypyranoindolidine compound [VII] or from a camptothecin compoundhaving 20-substituted hydroxy group [XV].

[0094] The o-acylaniline compound [IV] to be used in the abovecondensation reactions can be prepared by a process as shown in thefollowing reaction scheme-1:

[0095] wherein the symbols are as defined above.

[0096] That is, a hydroxyl compound [XXII] is treated with an oxidizing,agent (e.g. activated manganese dioxide, pyridinium dichromate) to givea ketone compound [XXIII], followed by subjecting it to a catalyticreduction in the presence of a suitable catalyst (e.g. palladium-carbon)in a suitable solvent to desired o-acylaniline compound [XIV]. Moreover,when the protecting group(s) in R⁵-R⁹ is/are removed by a catalyticreduction, the product may be again introduced with a protecting groupto give an o-acylaniline compound [XIV]. Besides, an o-acylanilinecompound [XV] wherein R⁵ is a lower alkyl group may also be prepared bytreating a hydroxyl compound [XXII] wherein R⁵ is a lower alkenyl groupwith an oxidizing agent, followed by catalytic reduction.

[0097] Furthermore, the hydroxyl compound [XXII] wherein the groupsR⁵-R⁹ have a protected amino group, a protected lower alkylamino group,a protected piperazino group, or a protected hydroxy group may also beprepared by introducing a protecting group to the corresponding compoundhaving unprotected group(s) by a conventional method.

[0098] The 2-halo-2-indolidinylacetic ester compound [III] used in thepresent invention is novel and can be prepared by a process as shown inthe following reaction scheme-2.

[0099] wherein the symbols are as defined above.

[0100] That is, an indolidine compound [XXIV] is reacted with a1,3-propanediol compound [XXV] in the presence of an acid (e.g.p-toluenesulfonic acid) or a Lewis acid (e.g. trimethylsilyl chloride)to give an indolidinylmethane compound [XXVI], and the compound [XXVI]is treated with a carboxylic diester [XXVII] in the presence of a base(e.g. sodium hydride, potassium t-butoxide) in a suitable solvent (e.g.toluene, tetrahydrofuran) to give a 2-indolidinylacetic ester compound[XXVIII], which is further halogenated by a conventional method to givethe desired 2-halo-2-indolidinylacetic ester compound [III].

[0101] Among the R type nitrogen-containing fused heterocycliccarboxylic acid compounds [IV] or a salt thereof, thenitrogen-containing fused heterocyclic carboxylic acid compound [XIX] ora salt thereof is novel and can be prepared by reacting anN-unsubstituted nitrogen-containing fused heterocyclic carboxylic acidcompound of the formula [XXIX]:

[0102] wherein the symbols are as defined above, or a salt thereof witha sulfonic acid of the formula [XXX]:

YOH  [XXX]

[0103] wherein the symbol is as defined above, or a reactive derivativeor salt thereof by a conventional sulfonamide forming reaction, forexample, by reacting a nitrogen-containing fused heterocyclic carboxylicacid compound [XXIX] and a halide (e.g. chloride) of a sulfonic acid[XXX] in the presence of a base (e.g. alkali metal hydroxide).

[0104] In the present description and claims, the term “S type” meansthat the absolute configuration at 2-position of a 2-substitutedhydroxy-2-indolidinylbutyric ester compound [II], a 2-substitutedhydroxy-2-(6-substituted aminomethylindolidinyl)butyric ester compound[V], a 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)butyric ester compound [VI] or a2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound [IX] or asalt thereof, or the absolute configuration at 4-position of a4-substituted hydroxypyranoindolidine compound [VII], a4-hydroxypyranoindolidine compound [VIII] or a salt thereof, a4-hydroxypyranoindolidine compound [X] or a salt thereof, a4-alkanoyloxypyranoindolidine compound [XII], or a4-alkanoyloxypyranoindolidine compound [XIII]; and the absoluteconfiguration at 2-position of a2-[(R)-N-tosylprolyloxy]-2-indolidinylbutyric ester compound [XXI] areall in “S” configuration.

[0105] Throughout the present description and claims, the term “loweralkyl” means a straight chain or branched chain alkyl group having 1 to6 carbon atoms, the term “lower alkanoyl group” and “lower alkanoicacid” mean a straight chain or branched chain alkanoyl group andalkanoic acid which have each 1 to 7 carbon atoms, respectively. Theterm “alkylene group” means a straight chain or branched chain alkylenegroup having 1 to 10 carbon atoms.

EXAMPLES

[0106] This invention is illustrated in more specifically by thefollowing examples and reference examples but should not be construed tobe limited thereto.

Example 1

[0107] (1) A mixture of ethyl2-bromo-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(22.21 g),(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (24.70 g) and potassium carbonate (5.11 g) in dimethylformamide(220 ml) is stirred at 60° C. for 70 minutes. The reaction mixture isextracted with ethyl acetate, and the extract is washed with a saturatedaqueous saline solution and dried over sodium sulfate. After distillingoff the solvent under reduced pressure, the residue is purified with asilica gel column chromatography (eluent; chloroform:ethylacetate=10:1→6:1) to give ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(35.41 g) as colorless powders.

[0108] Yield: 92%

[0109] IR (Nujol, cm⁻¹): 2220, 1750, 1665, 1615 MS (m/z): 738 (MH⁺) NMR(300 MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s), 1.10 and 1.15 (3H, t, J=7Hz), 1.33 and 1.35 (3H, s), 2.45-2.60 (2H, m), 3.25-3.40 (2H, m),3.61-3.76 (4H, m), 3.95-4.22 (4H, m), 4.58 and 4.68 (1H, d, J=16 Hz),4.72 and 4.75 (1H, d, J=16 Hz), 5.22 and 5.29 (1H, dd and t, J=3.6 and 5Hz), 6.01 and 6.04 (1H, s), 6.58 and 6.65 (1H, s), 7.02-7.20 (4H, m),7.37-7.51 (3H, m), 7.54-7.60 (2H, m), 7.62-7.68 (2H, m), 7.85-7.93 (2H,m).

[0110] (2) Ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(33.63 g) is dissolved in dry dimethylacetamide-toluene (1:1) (330 ml),and thereto is added a 60% oily dispersion of sodium hydride (2.21 g)(1.2 equivalent), and the mixture is stirred at room temperature for 75minutes. To the mixture is added ethyl iodide (36.5 ml) (10equivalents), and the mixture is further stirred at room temperatureovernight. The reaction mixture is extracted with ethyl acetate, and theextract is washed with an aqueous citric acid solution and an aqueoussaturated saline solution, dried over sodium sulfate-magnesium sulfate,and then treated with active carbon (5 g). After distilling off thesolvent under reduced pressure, the residue (35.69 g) [thediastereoselectivity of 2S compound and 2R compound=15.2:1.0 (88% d.e.)which is calculated based on the ratio of integral value at the peak ofδ:6.71 and 6.46 in NMR spectrum] is dissolved in acetone (60 ml), andthe mixture is stirred at room temperature, and thereto addedportionwise hexane (76 ml) and also added a seed crystal of the desireddiastereomer. The precipitated crystals are collected by filtration,washed with acetone-hexane (60:76) (about 100 ml) to give ethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(26.64 g) as colorless crystals.

[0111] Yield: 76%

[0112] m.p.: >82° C. (gradually decomposed) [α]_(D) ²⁶:−43.3° (c=1.02,chloroform) IR (Nujol, cm⁻¹): 2220, 1755, 1660, 1615 MS (m/z): 766 (MH⁺)NMR (300 MHz, CDCl₃, δ): 0.70 (3H, t, J=7.5 Hz), 0.85 (3H, brs), 1.02(3H, t, J=7 Hz), 1.21 (3H, brs), 2.16-2.55 (4H, m), 3.35 (1H, dd, J=6.5and 16 Hz), 3.50 (1H, dd, J=3 and 16 Hz), 3.55-3.70 (4H, m), 3.70-3.90(2H, m), 3.93-4.16 (2H, m), 4.68 (1H, d, J=16 Hz), 4.76 (1H, d, J=16Hz), 5.37 (1H, dd, J=3 and 6.5 Hz), 6.71. (1H, s), 7.02-7.10 (1H, m),7.10-7.20 (3H, m), 7.36-7.50 (3H, m), 7.54-7.59 (2H, m), 7.63-7.68 (2H,m), 7.89-7.96 (2H, m).

[0113] (3) Ethyl (2S)-2-[[((3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[(6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(23.71 g) and Raney nickel (W-4) (49 g) are dissolved in aceticanhydride-acetic acid (460 ml-190 ml), and the mixture is stirred underhydrogen atmosphere at 50-60° C. After completion of the reaction, thecatalyst is filtered off, and the filtrate is concentrated under reducedpressure, and the residue is purified with a silica gel columnchromatography (eluent; chloroform:methanol=100:1→70:1→60:1) to giveethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]-carbonyloxy]-2-[6-[(acetylamino)methyl]-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(22.10 g) as pale yellow powders.

[0114] Yield: 87%

[0115] [α]_(D) ²⁶:−14.9° (c=1.01, chloroform) IR (Nujol, cm⁻¹): 3405,3295, 1750, 1660 MS (m/z): 812 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.69 (3H,t, J=7.5 Hz), 0.88 (3H, s), 1.02 (3H, t, J=7 Hz), 1.24 (3H, s), 1.96(3H, s), 2.12-2.55 (4H, m), 3.31 (1H, dd, J=6.5 and 16 Hz), 3.41 (1H,dd, J=3 and 16 Hz), 3.59 (2H, s), 3.63 (2H, s), 3.84 (1H, dq, J=11 and 7Hz), 3.94-4.14 (3H, m), 4.54 (1H, dd, J=14 and 5.5 Hz), 4.58-4.68 (1H,m), 4.63 (1H, d, J=15 Hz), 4.71 (1H, d, J=15 Hz), 5.25 (1H, dd, J=3 and6.5 Hz), 6.74 (1H, s), 7.00-7.19 (5H, m), 7.37-7.50 (3H, m), 7.54-7.64(4H, m), 7.83-7.89 (2H, m).

[0116] (4) Ethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-[(acetylamino)methyl]-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(30.16 g) is dissolved in acetic anhydride-acetic acid (450 ml -150 ml),and thereto is added sodium nitrite (13.18 g) under ice cooling, and themixture is stirred on an ice-water bath for 4 hours. The reactionmixture is poured onto chloroform (1.5 liter), and undissolvedsubstances are filtered off. The filtrate is evaporated to dryness underreduced pressure, and the residue is mixed with ethyl acetate (900 ml),and the mixture is stirred at 60° C. for 13 hours. The reaction mixtureis diluted with ethyl acetate (700 ml), and the mixture is washed withwater and saline solution, dried over sodium sulfate and then treatedwith active carbon. After distilling off the solvent under reducedpressure, the residue is crystallized from ethyl acetate-hexane to giveethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(16.77 g) as colorless prisms.

[0117] Yield: 55%

[0118] m.p.: 145-148° C. [α]_(D) ²⁷:−9.6 (c=1.0, chloroform) IR (Nujol,cm⁻¹): 1755, 1659, 1614 MS (m/z): 813 (MH⁺) NMR (300 MHz, CDCl₃, δ):0.54 (3H, t, J=7.4 Hz), 0.88 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.30 (3H,s), 2.09 (3H, s), 2.24 (2H, q like, J=7.6 Hz), 2.47 (2H, t, J=7 Hz),3.27 (2H, m), 3.65 (4H, m), 3.91-4.17 (4H, m), 4.64 (1H, d, J=15.6 Hz),4.72 (1H, d, J=15.6 Hz), 5.13 (1H, dd, J=5.3 and 3 Hz), 5.25 (2H, s),6.65 (1H, s), 7.01-7.20 (4H, m), 7.37-7.50 (3H, m), 7.55-7.59 (2H, m),7.65 (2H, d like, J=8.6 Hz), 7.90 (2H, d like, J=8.6 Hz). (5) Ethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxyl]-2-[6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(1.457 g) is dissolved in a 80% aqueous trifluoroacetic acid solution(15 ml) under ice cooling, and the mixture is stirred at roomtemperature for 2 days. The reaction mixture is concentrated underreduced pressure, and the residue is extracted with. chloroform, and theextract is washed with water, and dried over magnesium sulfate. Theextract is distilled to remove the solvent under reduced pressure togive (4S)-7, 8-dihydro-4-ethyl-4-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione(1.145 g) as colorless foam.

[0119] Yield: 100%

[0120] IR (Nujol, cm⁻¹): 1746, 1661 MS (m/z): 639 (MH⁺) NMR (300 MHz,CDCl₃, δ): 0.82 (3H, t, J=7.5 Hz), 1.78-2.09 (4H, m), 2.66-2.90 (2H, m),3.23 (2H, d like, J=4.6 Hz), 4.07-4.27 (2H, m), 4.53 (1H, d, J=15.4 Hz),4.69 (1H, d, J=15.6 Hz), 5.01 (1H, t, J=5.2 Hz), 5.23 (1H, d, J=18 Hz),5.49 (1H, d, J=17.9 Hz), 6.58 (1H, s), 7.01-7.18 (4H, m), 7.38-7.56 (5H,m), 7.62 (2H, dlike, J=8.6 Hz), 7.89 (2H, d like, J=8.6 Hz).

[0121] (6) (4S)-7, 8-Dihydro-4-ethyl-4-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione(1.145 g) and1-[5′-(3″-(t-butoxycarbonylaminopropyloxy)-2′-aminophenyl]propan-1-one(867 mg) are dissolved in acetic acid (15 ml), and the mixture isstirred at 60° C. for 47 hours. The reaction mixture is concentratedunder reduced pressure, and the resulting crude product is purified witha silica gel column chromatography (eluent; chloroform: ethylacetate=2:1→1:1) and then recrystallized from ethyl acetate-hexane togive(20S)-7-ethyl-10-[3-(tert-butoxycarbonylamino)propyloxyl-20-O-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetralydro-3-isoquinolyl]carbonyl]camptotiecin(1.11 g) as colorless crystals.

[0122] Yield: 67%

[0123] m.p.: 213-216° C. IR (Nujol, cm⁻¹): 3407, 1763, 1753, 1709, 1669,1614 MS (m/z): 925 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.86 (3H, t, J=7.5Hz), 1.35 (3H, t, J=7.6 Hz), 1.46 (9H, s), 1.88-2.18 (4H, m), 2.94-3.20(2H, m), 3.34 (2H, d, J=4.8 Hz), 3.42 (2H, q like, J=6.4 Hz), 4.22 (2H,t, J=6 Hz), 4.57 (1H, d, J=15.4 Hz), 4.73-4.81 (1H, br), 4.81 (1H, d,J=15.4 Hz), 4.90 (1H, d, J=18.7 Hz), 5.09 (1H, d, J=18.7 Hz), 5.21 (1H,d, J=4.8 Hz), 5.26 (1H, d, J=17.2 Hz), 5.51 (1H, d, J=17.2 Hz), 6.99(1H, s), 7.01-7.18 (4H, m), 7.22-7.29 (2H, m), 7.30-7.42 (6H, m), 7.49(1H, dd, J=9.3 and 2.7 Hz), 7.89 (2H, d like, J=8.6 Hz), 8.20 (1H, d,J=9.2 Hz).

[0124] (7)(20S)-7-Ethyl-10-[3-(tert-butoxycarbonylamino)propyloxy]-20-O-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyl]-camptothecin(991 mg) is dissolved in water-methanol (6 ml -30 ml), and thereto isadded lithium hydroxide monohydrate (180 mg) under ice cooling, and themixture is stirred at room temperature for 22 hours and further stirredat 50° C. for 4 hours. The reaction mixture is concentrated underreduced pressure, and thereto are added chloroform (20 ml) and aceticacid (4 ml), and the mixture is stirred at room temperature for 19hours. The reaction mixture is diluted with chloroform and water, andthe chloroform layer is washed with water and an aqueous saturatedsaline solution, dried over sodium sulfate. The solvent is distilled,off under reduced pressure to give(20S)-7-ethyl-10-[3-(tert-butoxycarbonylamino)propyloxy]camptothecin.

[0125] (8) The obtained(20S)-7-ethyl-10-[3-(tert-butoxycarbonylamino)propyloxy]camptothecin isdissolved in water-ethanol (5 ml-15 ml) and thereto is added 6.6Nhydrochloric acid-ethanol (5 ml), and the mixture is stirred at roomtemperature for 23 hours. The reaction mixture is evaporated to drynessunder reduced pressure and the residue is dissolved in ethyl acetate andwater. The ethyl acetate layer is further extracted with water, and theaqueous layers are combined and evaporated to dryness under reducedpressure. The residue is crystallized from isopropanol-water to give(20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride (240 mg)as pale yellow needles.

[0126] Yield: 44% overall in the above (7) and (8)

[0127] m.p.:>218° C. (decomposed) [α]_(D) ²⁵:+9.8° (c=1.0, water) MS(m/z): 450 (M−Cl⁺) IR (Nujol, cm⁻¹): 3450, 3370, 1745, 1660 NMR (300MHz, DMSO-d₆, δ): 0.88 (3H, t, J=7 Hz), 1.32 (3H, t, J=8 Hz), 1.78-1.95(2H, m), 2.08-2.19 (2H, m), 3.0-3.1 (2H, m), 3.13-3.25 (2H, m), 4.32(2H, t, J=6 Hz), 5.32 (2H, s), 5.43 (2H, s), 7.28 (1H, s), 7.50-7.56(2H, m), 7.99 (3H, brs), 8.11 (1H, d, J=10 Hz).

Example 2

[0128] (1) The(4S)-7,8-dihydro-4-ethyl-4-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trioneobtained in Example 1-(5) is treated in the same manner as described inExample 1-(7) to give(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione.

[0129] (2) The(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trioneis treated in the same manner as described in Example 1-(6) and -(8) togive (20S)-7-ethyl-10-[3-aminopropyloxy)camptothecin hydrochloride asyellow powder.

Example 3

[0130] (1) Ethyl2-bromo-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(1.28 g),(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (1.63 g) and potassium carbonate (357 mg) are mixed indimethylformamide (15 ml), and the mixture is stirred at 70° C. for 20minutes. The reaction mixture is treated in the same manner as describedin Example 1-(1) to give ethyl2-[[(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(2.10 g) as colorless powders.

[0131] Yield: 99%

[0132] IR (Nujol, cm⁻¹): 2225, 1750, 1665, 1615 MS (m/z): 707 (MH⁺) NMR(300 MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s), 1.10 and 1.20 (3H, t, J=7Hz), 1.33 and 1.36 (3H, s), 2.54-2.63 (2H, m), 3.30-3.42 (2H, m),3.60-3.75 (4H, m), 4.00-4.22 (4H, m), 4.50 and 4.57 (1H, d, J=15 Hz),4.78 and 4.83 (1H, d, J=15 Hz), 5.22 and 5.32 (1H, dd, J=3 and 6 Hz),5.90 and 5.95 (1H, s), 6.48 and 6.54 (1H, s), 7.00-7.23 (4H, m), 8.01and 8.05 (2H, d, J=9 Hz), 8.29 and 8.31 (2H, d, J=9 Hz).

[0133] (2) Ethyl2-[[(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(25.09 g) is dissolved in dry dimethylacetamide-toluene (1:1) (240 ml),and the mixture is reacted in the same manner as described in Example1-(2) by using a 60% oily dispersion of sodium hydride (1680 mg) (1.2equivalent) and ethyl iodide (54.58 g) (10 equivalents), and the extractis washed with an aqueous citric acid solution and an aqueous saturatedsaline solution, dried over magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue is powdered from ethylacetate—diethyl ether to give ethyl2-[[(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(diastereomer mixture) (22.04 g) as colorless powders. Thediastereoselectivity of 2S compound and 2R compound=20.0:1.0 (90% d.e.)which is calculated based on the ratio of integral value at the peak of6:6.85 and 6.41 in NMR spectrum. The colorless powders arerecrystallized from isopropanol to give a pure product (19.32 g) ascolorless crystals.

[0134] Yield: 75%

[0135] m.p.: 181-182° C. [α]_(D) ²⁶:−128.39° (c=0.5, chloroform) IR(Nujol, cm⁻¹): 2217, 1755, 1665, 1615 MS (m/z): 735 (MH⁺) NMR (300 MHz,CDCl₃, δ): 0.77 (3H, t, J=7.5 Hz), 0.85 (3H, s), 0.89 (3H, t, J=7 Hz),1.20 (3H, s), 2.13 (1H, dq, J=7.3 and 15 Hz), 2.27 (1H, dq, J=7.3 and 15Hz), 2.52-2.57 (2H, m), 3.45-3.66 (7H, m), 3.80-3.90 (1H, m), 4.16 (1H,dq, J=7.3 and 13 Hz), 4.36 (1H, dq, J=7.3 and 13 Hz), 4.52 (1H, d, J=15Hz), 4.87 (1H, d, J=15 Hz), 5.48 (1H, dd, J=3 and 6 Hz), 6.85 (1H, s),7.00-7.10 (1H, m), 7.12-7.23 (3H, m), 8.05 (2H, d, J=9 Hz), 8.24 (2H, d,J=9 Hz).

[0136] (3) The compound obtained in the above (2) is treated in the samemanner as described in Example 1-(3)-(8) or in Example 1-(3)-(5), (7),(6) and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Example 4

[0137] (1) Ethyl2-bromo-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(363 mg),(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (472 mg) and potassium carbonate (95 mg) are mixed indimethylformamide (4 ml), and the mixture is stirred at 70° C. for 40minutes. The reaction mixture is treated in the same manner as describedin Example 1-(1) to give ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-(6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(579 mg) as colorless powders.

[0138] Yield=94%

[0139] IR (Nujol, cm⁻¹): 2225, 1750, 1665, 1615 MS (m/z): 766 (MH⁺) NMR(300 MHz, CDCl₃, δ): 0.84 (3H, t, J=7.5 Hz), 0.94 (3H, t, J=7.5 Hz),1.11 and 1.16 (3H, t, J=7 Hz), 1.20-1.30 (2H, m), 1.77-1.86 (2H, m),2.45-2.60 (2H, m), 3.27-3.40 (2H, m), 3.60-3.65 (2H, m), 3.75-3.90 (2H,m), 4.00-4.20 (4H, m), 4.55 and 4.80 (2H, m), 5.21 and 5.28 (1H, dd, J=3and 6 Hz), 6.02 and 6.06 (1H, s), 6.57 and 6.63 (1H, s), 7.00-7.20 (4H,m), 7.40-7.70 (7H, m), 7.88 and 7.90 (2H, d, J=8 Hz).

[0140] (2) Ethyl 2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(564 mg) is dissolved in dry dimethylformamide (5 ml), and the mixtureis reacted in the same manner as described in Example 1-(2) by using a60% oily dispersion of sodium hydride (35 mg) (1.2 equivalent) and ethyliodide (1150 mg) (10 equivalents) to give ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate(diastereomer mixture) (522 mg) as colorless powders. Thediastereoselectivity of 2S compound and 2R compound=10.8:1.0 (83% d.e.)which is calculated based on the ratio of integral value at the peak ofδ:6.67 and 6.43 in NMR spectrum.

[0141] IR (Nujol, cm⁻¹): 2220, 1750, 1660, 1615 MS (m/z): 794 (MH⁺) NMR(300 MHz, CDCl₃, δ): 0.69 (3H, t, J=7.5 Hz), 0.81 (3H, t, J=7.5 Hz),0.87 (3H, t, J=7.5 Hz), 1.03 (3H, t, J=7 Hz), 1.22 (2H, q, J=7.5 Hz),1.67 (2H, q, J=7.5 Hz), 2.20-2.45 (4H, m), 3.34 (1H, dd, J=6.5 and 16Hz), 3.48-3.58 (3H, m), 3.70-3.85 (4H, m), 3.98-4.10 (2H, m), 4.67 (1H,d, J=15 Hz), 4.76 (1H, d, J=15 Hz), 5.36 (1H, dd, J=3 and 6.5 Hz), 6.43and 6.67 (1H, s), 7.00-7.20 (4H, m), 7.40-7.50 (3H, m), 7.56 (2H, d, J=8Hz), 7.65 (2H, d, J=9 Hz), 7.92 (2H, d, S=9 Hz).

[0142] (3) The compound obtained in the above (2) is treated in the samemanner as described in Example 1-(3)-(8) or in Example 1-(3)-(5), (7),(6) and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Example 5

[0143] (1) Ethyl(2S)-2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-acetoxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrateobtained in Example 1-(4) (1.00 g) is dissolved inwater-methanol-tetrahydrofuran (5 ml+20 ml+5 ml), and thereto is addedlithium hydroxide monohydrate (265 mg), and the mixture is stirred atroom temperature for one hour to give lithium(2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrate.

[0144] (2) Lithium(2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrateobtained above is dissolved in chloroform (20 ml) and acetic acid (4ml), and the mixture is stirred at room temperature for 16 hours, and tothe reaction mixture is added water, and the mixture is extracted withchloroform three times. The extract is washed with an aqueous saturatedsaline solution, dried over sodium sulfate, and distilled under reducedpressure. The residue is purified by silica gel column chromatography(eluent, chloroform) and recrystallized from ethyl acetate to give(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,10-dione(276 mg) as colorless needles.

[0145] Yield: 64% over all in the above (1) and (2)

[0146] m.p.: 208-210° C. [α]_(D) ²⁷:+88.2° (c=0.99, chloroform) IR(Nujol, cm⁻¹): 3340, 2924, 1744 MS (m/z): 350 (MH⁺) NMR (300 MHz, CDCl₃,δ): 0.88 (3H, s), 0.99 (3H, t, J=7.3 Hz), 1.29 (3H, s), 1.70-1.92 (2H,m), 2.54 (2H, t, J=7.0 Hz), 3.65-3.69 (4H, m), 3.71 (1H, s), 4.14 (2H,dt, J=3.7 and 7.0 Hz), 5.17 (1H, d, J=16.2 Hz), 5.60 (1H, d, J=16.2 Hz),6.81 (1H, s).

[0147] (3) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano[3,4-]indolidine-3,10-dioneis treated in the same manner as described in Example 1-(5) to give(4S)-7,8-dihydro4-ethyl-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione.

[0148] (4) The(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]-indolidine-3,6,10(4H)-trioneis treated in the same manner as described in Example 1-(6) and (8) togive (20S)-7-ethyl-10-[3-(aminopropyloxy)camptothecin hydrochloride.

Example 6

[0149] (1) Lithium(2S)-2-hydroxy-2-[6-hydroxymethyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]butyrateobtained in Example 5-(1) is treated in the same manner as described inExample 1-(5) to give(4S)-7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione.

[0150] (2) The (4S)-7, 8-dihydro-4-ethyl-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trione is treated in the same manner asdescribed in Example 1-(6) and (8) to give(20S)-7-ethyl-10-[³-(aminopropyloxy)camptothecin hydrochloride.

Example 7

[0151] (1) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-hydroxy-1H-pyrano[3,4-f]indolidine-3,10-dioneobtained in Example 5-(2) (50 mg) is dissolved in acetic anhydride (1ml), and thereto are added pyridine (1 ml) and4-N,N-dimethylaminopyridine (4 mg) under ice cooling, and the mixture isstirred at room temperature for 23 hours. The reaction mixture isdiluted with chloroform, and the mixture is washed with an aqueouscitric acid solution, water and an aqueous saturated saline solution,and dried over sodium sulfate. After distilling off the solvent underreduced pressure, the residue is purified by silica gel columnchromatography (eluent, chloroform:methanol=40:1) to give(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltrimethylenedioxy)-4-acetoxy-1H-pyrano[3,4-f]indolidine-3,10-dione(56 mg) as colorless crystals.

[0152] Yield: 99%

[0153] m.p.: 185-188° C. IR (Nujol, cm⁻¹): 2922, 2852, 1743, 1671, 1613MS (m/z): 392 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 0.91 (3H, t,J=7.5 Hz), 1.28 (3H, s), 1.95-2.10 (1H, m), 2.15 (3H, s), 2.15-2.28 (1H,m), 2.40-2.61 (2H, m), 3.55-3.73 (4H, m), 4.12 (2H, t, J=6.8 Hz), 5.27(1H, d, J=17.1 Hz), 5.52 (1H, d, J=17 Hz), 6.31 (1H, s).

[0154] (2) The(4S)-7,8-dihydro-4-ethyl-6,6-(2,2-dimethyltmethylenedioxy)-4-acetoxy-1H-pyrano[3,4-f]indolidine-3,10-dioneis treated in the same manner as described in Example 1-(5) to give(4S)-7,8-dihydro-4-ethyl-4-acetoxy-1H-pyrano[3,4-f]indolidine-3,6,10(4H)-trioneas colorless crystals.

[0155] m.p.: 197-203° C. IR (Nujol, cm⁻¹): 1742, 1732, 1661, 1610 ESI-MS(0.02M ammonium acetate/methanol, m/z): 323 (MNH₄ ⁺) NMR (300 MHz,CDCl₃, δ): 0.92 (3H, t, J=7.5 Hz), 1.94-2.25 (2H, m), 2.16 (3H, s), 2.95(2H, t, J=6.9 Hz), 4.32 (2H, td, J=6.9 and 0.8 Hz), 5.33 (1H, dd, J=18.1and 0.5 Hz), 5.60 (1H, dd, J=18.1 and 0.4 Hz), 6.76 (1H, s).

[0156] (3) The(4S)-7,8-dihydro-4-ethyl-4-acetoxy-1H-pyrano[3,4-f]-indolidine-3,6,10(4H)-trioneis treated in the same manner as described in Example 1-(6) to give(20S)-20-O-acetyl-7-ethyl-10-[3-(tert-butoxycarbonylamino)propyloxy]camptothecinas colorless powders.

[0157] m.p.: 173-176° C. IR (Nujol, cm⁻¹): 3370, 1765, 1749, 1696, 1657ESI-MS (m/z): 592 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.97 (3H, t, J=7.5 Hz),1.39 (3H, t, J=7.71 Hz), 1.45 (9H, s), 2.05-2.32 (4H, m), 2.21 (3H, s),3.14 (2H, q, J=7.7 Hz), 3.41 (2H, q like, J=6.3 Hz), 4.21 (2H, t, J=6.1Hz), 4.77 (1H, br), 5.23 (2H, d, J=1.1 Hz), 5.40 (1H, d, J=17.2 Hz),5.68 (1H, d, J=17.2 Hz), 7.15 (1H, s), 7.33 (1H, d, J=2.6 Hz), 7.47 (1H,dd, J=9.2 and 2.7 Hz), 8.12 (1H, d, J=9.3 Hz).

[0158] (4) The(20S)-20-O-acetyl-7-ethyl-10-[3-(tert-butoxycarbonylamino)propyloxy]camptothecinis treated in the same manner as described in Example 1-(7) and (8) togive (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride.

Examples 8-12

[0159] (1) The corresponding starting compounds are treated in the samemanner as described in Example 1-(1) and (2), there are prepared thecompounds as shown in the following Table 1. TABLE 1

Diastereoselectivety Ex. No. X 2S:2R  8(1) —Cl 9.5:1.0  9(1) —CH₃9.0:1.0 10(1) —OCH₃ 9.0:1.0 11(1)

9.5:1.0 12(1)

10.1:1.0 

[0160] (2) The compounds obtained in the above (1) are treated in thesame manner as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7),(6) and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Examples 13-16

[0161] (1) The corresponding starting compounds are treated in the samemanner as described in Example 1-(1) and (2), there are prepared thecompounds as shown in the following Table 2. TABLE 2

Ex. No. R⁰ 13(1)

14(1)

15(1)

16(1)

[0162] (2) The compounds obtained in the above (1) are treated in thesame manner as described in Example 1-(3)-(8) or Example 1-(3)-(5), (7),(6) and (8) to give (20S)-7-ethyl-10-(3-aminopropyloxy)camptothecinhydrochloride.

Examples 17-23

[0163] The corresponding starting compounds are treated in the same asdescribed in Examples 1, 2, 5 or 7, there are prepared the compounds inthe following Table 3. TABLE 3

Ex. No. R⁵¹ R⁶¹ R⁷¹ R⁸¹ R⁹¹ 17

—H —O(CH₂)₂O— —H 18 —CH₂NH₂ —H —O(CH₂)₂O— —H 19 —CH₂NH₂ —H —OCH₂O— —H 20—H —NH₂ —H —H —H 21

—CH3 —F —H 22 —(CH₂)3— —O(CH₂)₃NH₂ —H —H 23 —H —H —O(CH₂)₃NH₂ —H —H

Example 24

[0164] (1) A mixture of ethyl2-chloro-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(34.11 g),(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (42.33 g) and potassium carbonate (8.67 g) in dimethylformamide(350 ml) is stirred at 60° C. for 45 minutes. The reaction mixture isice-cooled, diluted with ethyl acetate (200 ml), and thereto is added anaqueous saturated sodium hydrogen carbonate solution (300 ml) and isfurther adder water (500 ml). The mixture is extracted with ethylacetate, and the extract is washed, dried, treated with active carbonand filtered. The solvent is distilled off to give ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(66.20 g) as pale yellow foam.

[0165] IR (Nujol, cm⁻¹): 2220, 1750, 1665, 1615 MS (m/z): 738 (MH⁺) NMR(300 MHz, CDCl₃, δ): 0.89 and 0.90 (3H, s), 1.10 and 1.15 (3H, t, J=7Hz), 1.33 and 1.35 (3H, s), 2.45-2.60 (2H, m), 3.25-3.40 (2H, m),3.61-3.76 (4H, m), 3.95-4.22 (4H, m), 4.58 and 4.68 (1H, d, J=16 Hz),4.72 and 4.75 (1H, d, J=16 Hz), 5.22 and 5.29 (1H, dd and t, J=3.6 and 5Hz), 6.01 and 6.04 (1H, s), 6.58 and 6.65 (1H, s), 7.02-7.20 (4H, m),7.37-7.51 (3H, m), 7.54-7.60 (2H, m), 7.62-7.68 (2H, m), 7.85-7.93 (2H,m).

[0166] (2) The ethyl2-[[(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolyl]carbonyloxy]-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetateobtained in the above (1) is treated in the same manner as described inExample 1-(2)-(8) to give(20S)-7-ethyl-10-(3-aminopropyloxy)camptothecin hydrochloride.

Reference Example 1

[0167] (1) 6-Cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydroindolidine (1.0g), 2,2-dimethyl-1,3-propanediol (6.64 g) and p-toluenesulfonic acid (15ml) are mixed in dichloroethane (25 ml), and the mixture is heated underreflux for 17 hours with a reflux apparatus provided with Dean-Starkdehydrating device. The reaction mixture is washed with an aqueoussaturated sodium hydrogen carbonate solution and an aqueous saturatedsaline solution, and dried over magnesium sulfate. After distilling offthe solvent under reduced pressure, the residue is purified with asilica gel column chromatography (eluent; chloroform:methanol=50:1) andrecrystallized from methanol to give6-cyano-7-methyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(1.05 g) as colorless needles.

[0168] Yield: 72% m.p.: 225-226° C. IR (Nujol, cm⁻¹): 2222, 1645, 1610MS (m/z): 275 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 1.30 (3H,s)2.49 (3H, s), 2.53 (2H, t, J=7 Hz), 3.62 (2H, d, J=11 Hz), 3.69 (2H,d, J=11 Hz), 4.15 (2H, t, J=7 Hz), 6.42 (1H, s).

[0169] (2) The6-cyano-7-methyl-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(14.43 g) is mixed in dry toluene (300 ml) and thereto is added a 60%oily dispersion of sodium hydride (9.26 g, 4.4 equivalents), and themixture is stirred on a bath of 80° C. for 2 hours. To the reactionmixture are added diethyl carbonate (24.85 g, 4 equivalents) and ethanol(0.97 g, 0.4 equivalent), and the mixture is reacted at 80° C. for 3hours. While cooling the reaction mixture on an ice bath, a 50% aceticacid (80 ml) is added thereto. The mixture is extracted with chloroform,and the extract is washed with an aqueous saturated saline solution, anddried over magnesium sulfate. After distilling off the solvent underreduced pressure, the residue is purified with a silica gel columnchromatography (eluent; chloroform:ethyl acetate=4:1) and recrystallizedfrom ethyl acetate-ether to give ethyl2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(14.63 g) as colorless needles.

[0170] Yield: 80% m.p.: 150-151° C. IR (Nujol, cm⁻¹): 2220, 1725, 1650,1610 MS (m/z): 347 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.87 (3H, s), 1.28(3H, s), 1.29 (3H, t, S=7.5 Hz), 2.54 (2H, t, J=7 Hz), 3.62 (2H, d, J=11Hz), 3.68 (2H, d, J=11 Hz), 3.79 (2H, s), 4.16 (2H, t, J=7 Hz), 4.22(2H, q, J=7 Hz), 6.54 (1H, s)

[0171] (3) The ethyl2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(14.60 g) is added to a suspension of a 60% oily dispersion of sodiumhydride (2.02 g, 1.2 equivalent) in dry tetrahydrofuran (240 ml), andthe mixture is stirred at room temperature for 3 hours. To the reactionmixture is added bromine (8.76 g, 1.3 equivalent), and the mixture isstirred at room temperature for 2 hours, and thereto is added ice water.The mixture is extracted with chloroform, and the extract is washed withan aqueous sodium thiosulfate solution and an aqueous saturated salinesolution, and dried over magnesium sulfate. After distilling off thesolvent under reduced pressure, the residue is purified with a silicagel column chromatography (eluent; chloroform:ethyl acetate=4:1) andrecrystallized from ethyl acetate-ether to give ethyl2-bromo-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(15.66 g) as colorless needles.

[0172] Yield: 87% m.p.: 117-119° C. IR (Nujol, cm⁻¹): 2217, 1725, 1650,1610 MS (m/z): 427 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.89 (3H, s), 1.28(3H, s), 1.32 (3H, t, J=7 Hz), 2.54 (2H, t, J=7 Hz), 3.65 (2H, d, J=12Hz), 3.67 (2H, d, J=12 Hz), 4.09-4.22 (2H, m), 4.24-4.35 (2H, m), 5.61(1H, s), 6.90 (1H, s).

Reference Example 2

[0173] (1) 6-Cyano-7-methyl-1,5-dioxo-1,2,3,5-tetrahydroindolidine (5.93g), 2,2-diethyl-1,3-propanediol (49.97 g) and p-toluenesulfonic acid(180 ml) are mixed in dichloroethane (150 ml), and the mixture is heatedunder reflux for 22 hours with a reflux apparatus provided withDean-Stark dehydrating device. The reaction mixture is treated in thesame manner as described in Reference Example 1-(1) and recrystallizedfrom methanol to give6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(6.67 g) as colorless needles.

[0174] Yield: 70% m.p.: 197-198° C. IR (Nujol, cm⁻¹): 2219, 1655, 1610MS (m/z): 303 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5 Hz),0.92 (3H, t, J=7.5 Hz), 1.22 (2H, q, J=7.5 Hz), 1.78 (2H, q, J=7.5 Hz),2.49 (3H, s), 2.52 (2H, t, J=7 Hz), 3.64 (2H, d, J=11 Hz), 3.78 (2H, d,J=11 Hz), 4.14 (2H, t, J=7 Hz), 6.39 (1H, s).

[0175] (2) The procedure of Reference Example 1-(2) is repeated by using6-cyano-7-methyl-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolidine(4.75 g), dry toluene (80 ml), a 60% oily dispersion of sodium hydride(2.76 g, 4.4 equivalents), diethyl carbonate (7.42 g, 4 equivalents) andethanol (0.37 ml, 0.4 equivalent), and the product is recrystallizedfrom ethyl acetate-ether to give ethyl2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(3.71 g) as colorless needles.

[0176] Yield: 63% m.p.: 127-129° C. IR (Nujol, cm⁻¹): 2220, 1745, 1660,1605 MS (m/z): 375 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5Hz), 0.91 (3H, t, J=7.5 Hz), 1.23 (2H, q, J=7.5 Hz), 1.29 (3H, t, J=7.5Hz), 1.75 (2H, q, J=7.5 Hz), 2.53 (2H, t, J=7 Hz), 3.62 (2H, d, J=12Hz), 3.77 (2H, d, J=12 Hz), 3.79 (2H, s), 4.15 (2H, t, J=7 Hz), 4.22(2H, q, J=7 Hz), 6.50 (1H, s).

[0177] (3) The ethyl2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(3.52 g) is added to a suspension of a 60% oily dispersion of sodiumhydride (451 mg, 1.2 equivalent) in dry tetrahydrofuran (60 ml), and themixture is treated at room temperature for 3 hours. To the reactionmixture is added bromine (1.95 g, 1.3 equivalent), and the mixture isstirred at room temperature for 3 hours, and the reaction mixture istreated in the same manner as described in Reference Example 1-(3) andrecrystallized from ethyl acetate-ether to give ethyl2-bromo-2-[6-cyano-1,1-(2,2-diethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(2.45 g) as colorless needles.

[0178] Yield: 58% m.p.: 106-108° C. IR (Nujol, cm⁻¹): 2220, 1735, 1660,1610 MS (m/z): 455 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.83 (3H, t, J=7.5Hz), 0.92 (3H, t, J=7.5 Hz), 1.26 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7Hz), 1.73 (2H, q, J=7.5 Hz), 2.52 (2H, t, J=7 Hz), 3.61 (1H, d, J=12Hz), 3.62 (1H, d, J=12 Hz), 3.77 (1H, dd, J=2 and 12 Hz), 3.80 (1H, dd,J=2 and 12 Hz), 4.16 (2H, m), 4.25-4.35 (2H, m), 5.61 (1H, s), 6.85 (1H,s).

Reference Example 3

[0179] Sodium hydroxide (13.6 g) is dissolved in water (300 ml), andtherein is suspended (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (30.0 g) and thereto is added tetrahydrofuran (120 ml). To theresulting solution is added 4-biphenylylsulfonyl chloride (42.9 g), andthe mixture is stirred at room temperature for one hour. The reactionmixture is acidified with 10% hydrochloric acid under ice cooling, andis diluted with water, and then extracted twice with ethyl acetate. Theextract is washed with water and an aqueous saturated saline solution,dried over sodium sulfate and then treated with active carbon.Undissolved materials are filtered off from the extract, and the solventis distilled off under reduced pressure. The residue is recrystallizedfrom ethyl acetate-hexane to give(3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (36.5 g) as colorless crystals.

[0180] Yield: 55% m.p.: 195-202° C. [α]_(D) ²⁹:+8.02° (c=1.08,dimethylformamide) IR (Nujol, cm⁻¹): 3300, 2924, 1743, 1456 MS (m/z):394 (MH⁺) NMR (300 MHz, CDCl₃, δ): 3.10-3.15 (2H, m), 4.48 (1H, d,J=15.6 Hz), 4.67 (1H, d, J=15.6 Hz), 4.93 (1H, dd, J=4.0 and 5.3 Hz),6.95-7.20 (4H, m), 7.40-7.53 (3H, m), 7.56-7.69 (4H, m), 7.83-7.88 (2H,m).

Reference Example 4

[0181] (3R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid (5.32 g)and sodium hydroxide (2.40 g) are added to a mixture of methylenechloride-water (200 ml -200 ml)) and thereto is added dropwise asolution of 4-nitrophenylsulfonyl chloride (6.62 g) in methylenechloride (100 ml) under ice cooling over a period of 30 minutes. Themixture is stirred under ice cooling for 3 hours, and thereto arefurther added sodium hydroxide (1.20 g) and a solution of4-nitrophenylsulfonyl chloride (3.32 g) in methylene chloride (60 ml) inthis order. The mixture is stirred under ice cooling for 2 hours, andfurther stirred at room temperature for 17 hours, and the reactionmixture is diluted with chloroform and 10% hydrochloric acid. Thechloroform layer is collected and washed with water and then with anaqueous saturated saline solution, dried over sodium sulfate and thentreated with active carbon. Undissolved materials are filtered off fromthe chloroform layer, and the solvent is distilled off under reducedpressure. The residue is purified with a silica gel columnchromatography (eluent, chloroform) and recrystallized from ethylacetate-hexane to give(3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid (4.01 g) as colorless crystals.

[0182] Yield: 37% m.p.: 140° C. [α]_(D) ²⁵:+27.2° (c=0.5, ethanol) IR(Nujol, cm⁻¹): 3316, 1743, 1531, 1169 MS (m/z): 361 (M−H⁺) NMR (300 MHz,CDCl₃, δ): 3.15-3.30 (2H, m), 4.40 (1H, d, J=15 Hz), 4.73 (1H, d, J=15Hz), 5.01 (1H, dd, J=3.7 and 5.7 Hz), 7.04-7.20 (4H, m), 7.99 (2H, d,J=9.0 Hz), 8.20 (2H, d, J=9.0 Hz).

Reference Example 5

[0183] To a suspension of ethyl2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(43.41 g) in tetrahydrofuran (600 ml) is added triethylamine (13.94 g)under argon atmosphere at −4° C. and thereto is further added dropwisetrimethylsilyl chloride (14.41 g) at −4 to −3° C. over a period of 5minutes. The mixture is stirred at the same temperature for 55 minutesand thereto is added dropwise a suspension of N-chlorosuccinimide (17.00g) in tetrahydrofuran (400 ml) at −4 to 4° C. over a period of 7minutes. The reaction mixture is further stirred at a temperature of 0°C. to 4° C. for 4.5 hours, and thereto added water (1 liter) at 0° C.,and the mixture is extracted with ethyl acetate. The extract is washed,dried, treated with active carbon, filtered and then distilled to removethe solvent. The residue is recrystallized from ethyl acetate-isopropylether to give ethyl2-chloro-2-[6-cyano-1,1-(2,2-dimethyltrimethylenedioxy)-5-oxo-1,2,3,5-tetrahydro-7-indolidinyl]acetate(40.28 g) as colorless needles.

[0184] Yield: 84% m.p.: 153-155° C. IR (Nujol, cm⁻¹): 2227, 1749, 1662,1615, 1541, 1311, 1241, 1202, 1179, 1161, 1143, 1065, 967, 835, 715APCIMS (m/z): 381 and 383 (MH⁺) NMR (300 MHz, CDCl₃, δ): 0.88 (3H, s),1.28 (3H, s), 1.31 (3H, t, J=7.1 Hz), 2.52-2.58 (2H, m), 3.60-3.70 (4H,m), 4.13-4.21 (2H, m), 4.22-4.37 (2H, m), 5.63 (1H, s), 6.77 (1H, s).

Reference Example 6

[0185] (1) 3-Aminopropanol (6.0 g) is dissolved in methylene chloride(50 ml) and thereto is added dropwise di-t-butyl dicarbonate (18.3 g)with stirring under ice cooling. The mixture is stirred at roomtemperature for 2 hours, and the reaction mixture is concentrated andthen purified with a silica gel column chromatography to give3-t-butoxycarbonylaminopropanol (13.98 g) as colorless oil.

[0186] Yield: 99.9% IR (Neat), ν_(max) cm⁻¹:3380, 1790 MS (m/z): 176(M+H⁺) NMR (300 MHz, CDCl₃, δ): 1.45 (9H, s), 1.62-1.72 (2H, m), 3.0(1H, brs.), 3.29 (2H, dd, J=12 Hz and 6 Hz), 3.66 (2H, dd, J=12 Hz and 6Hz), 4.80 (I1H, brs).

[0187] (2) 3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved inmethylene chloride (100 ml) and thereto are added triethylamine (8.66 g)and tosyl chloride (16.3 g) with stirring under ice cooling. The mixtureis stirred at room temperature overnight. The reaction mixture isconcentrated and the residue is dissolved in water-ethyl acetate, andthe organic layer is separated, washed with an aqueous saturated salinesolution, dried over sodium sulfate, and then distilled off the solvent.The residue is purified with a silica gel column chromatography to give3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as pale yellow oil.

[0188] Yield: 82% IR (Neat), ν_(max) cm⁻¹:3400, 3340, 1700, 1600 MS(m/z): 352 (M+Na⁺) NMR (300 MHz, CDCl₃, δ): 1.42 (9H, s), 1.78-1.90 (2H,m), 2.45 (3H, s), 3.11-3.22 (2H, m), 4.09 (2H, t, J=6 Hz), 4.5-4.65 (1H,m), 7.36 (2H, d, J=8 Hz), 7.77-7.83 (2H, m.

[0189] (3) 5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in drytetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesiumbromide (2.3 equivalents) with stirring at −78° C. The temperature ofthe reaction mixture is raised gradually. After completion of thereaction, 1N HCl is added to the reaction mixture, and the mixture isextracted with ethyl acetate, and the organic layer is separated, washedwith an aqueous saturated saline solution, dried over sodium sulfate,and then distilled off the solvent. The residue is purified with asilica column chromatography to give1-(5′-hydroxy-2′-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brownpowders.

[0190] Yield: 73% m.p.: 126-130° C. IR (Nujol), ν_(max) cm⁻¹: 3440, 1600MS (m/z): 195 (M⁺) NMR (300 MHz, CDCl₃, δ): 2.4 (1H, br), 5.19 (1H, dd,J=10.5 Hz and 1.5 Hz), 5.38 (1H, dd, J=17 Hz and 1.5 Hz), 5.89 (1H, m),6.08 (1H, ddd, J=17 Hz, 10.5 Hz and 5 Hz), 6.80 (1H, dd, J=9 Hz and 3Hz), 7.22 (1H, d, J=3 Hz), 7.97 (1H, d, J=9 Hz), 9.90 (1H, brs).

[0191] (4) 1-(5′-Hydroxy-2′-nitrophenyl)-2-propen-1-ol (2.0 g) isdissolved in dry dimethylformamide (100 ml) and thereto are added sodiumiodide (1 equivalent) and potassium carbonate and3-t-butoxycarbonylaminopropyl tosylate (1.5 equivalent). The mixture isstirred at 50° C. for 6 hours, and thereto is added ethyl acetate. Themixture is washed with an aqueous saturated saline solution, dried oversodium sulfate. After distilling off the solvent, the residue ispurified with a silica gel column chromatography to give1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl]-2-propen-1-ol(3.53 g) as pale brown caramel.

[0192] Yield: 98% IR (Neat), ν_(max) cm⁻¹:3400, 1690, 1680 MS (m/z): 375(M+Na⁺) NMR (300 MHz, CDCl₃, δ): 1.44 (9H, s), 1.96-2.06 (2H, m), 2.80(1H, brs), 3.33 (2H, q, J=6.5 Hz), 4.11 (2H, t, J=6 Hz), 4.8 (1H, brs),5.24 (1H, dd, J=10.5 Hz and 1.5 Hz), 5.42 (1H, dd, J=17 Hz and 1.5 Hz),5.92 (1H, d, J=5 Hz), 6.08 (1H, ddd, J=17 Hz, 10.5 Hz and 5 Hz), 6.86(1H, dd, J=9 Hz and 3 Hz), 7.25 (1H, d, J=3 Hz), 8.04 (1H, d, J=9 Hz).

[0193] (5)1-(5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl)-2-propen-1-ol(9.66 g) is dissolved in chloroform (300 ml) and thereto is addedactivated manganese dioxide (7.2 g), and the mixture is heated withreflux. After completion of the reaction, inorganic materials arefiltered off with celite, and the filtrate is concentrated, and theretois added ethyl acetate. The organic layer is separated, washed with anaqueous saturated saline solution, dried over sodium sulfate. Afterdistilling off the solvent, the residue is purified with a silica gelcolumn chromatography to give1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl]-2-propen-1-one(6.01 g) as yellow color crystal.

[0194] m.p.: 65-71° C. Yield: 63% IR (Neat), ν_(max) cm⁻¹:3350, 1700 MS(m/z): 351 (M+H⁺) NMR (300 MHz, CDCl₃, δ): 1.44 (9H, s), 1.98-2.18 (2H,m), 3.28-3.37 (2H, q, J=6.5 Hz), 4.08-4.16 (2H, m), 4.67 (1H, brs), 5.85(1H, d, J=17.5 Hz), 6.02 (1H, d, J=10.5 Hz), 6.62 (1H, dd, J=17.5 Hz and10.5 Hz), 6.82 (1H, d, J=3 Hz), 7.03 (1H, dd, J=9 Hz and 3 Hz), 8.17(1H, d, J=9 Hz).

[0195] (6)1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitroptenyl)-2-propen-1-one(325 mg) is dissolved in ethanol (15 ml) and thereto is added 10%palladium-carbon (40 mg), and the mixture is stirred under hydrogenatmosphere for 1.5 hour. After removing the catalyst by filtration, thefiltrate is concentrated and purified with a silica gel columnchromatography to give1-(5′-(3″-t-butoxy-carbonylaminopropyloxy)-2′-aminophenyl]propan-1-one(248 mg) as yellow powders.

[0196] m.p.: 112-115° C. Yield: 83% IR (Nujol), ν_(max) cm⁻¹:3450, 3400,3340, 1700, 1650 MS (m/z): 323 (M+H⁺) NMR (300 MHz, CDCl₃, δ): 1.21 (3H,t, J=7 Hz), 1.45 (9H, s), 1.90-2.01 (2H, m), 2.95 (2H, q, J=7.5 Hz),3.33 (2H, q, J=6.5 Hz), 3.97 (2H, t, J=6.5 Hz), 4.48 (1H, brs), 5.96(2H, brs), 6.62 (1H, d, J=9 Hz), 6.95 (1H, dd, J=9 Hz and 3 Hz), 7.24(1H, d, J=3 Hz).

What is claimed is:
 1. A process for preparing an S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound of the formula [II]:

wherein R⁰ is a residue of a nitrogen-containing fused heterocycliccarboxylic acid having an absolute configuration of “R” which isobtained by removing hydroxy group from the carboxyl group of saidcarboxylic acid (in which the nitrogen atom contained in the residue isprotected), R¹ and R² are a lower alkyl group, and E is an esterresidue, which comprises reacting a 2-halo-2-indolidinylacetic estercompound of the formula [III]:

wherein x is a halogen atom, and R¹, R² and E are as defined above, withan R type nitrogen-containing fused heterocyclic carboxylic acidcompound of the formula [IV]: wherein R^(o) is as defined above, or asalt thereof to give a 2-substituted hydroxy-2-indolidinylacetic estercompound of the formula [I]:

wherein the symbols are as defined above, and then ethylating 2-positionof the resultant compound [I].
 2. A process for preparing an S type4-hydroxypyranoindolidine compound of the formula [VIII]:

or a salt thereof, which comprises subjecting the S type 2-substitutedhydroxy-2-indolidinylbutyric ester compound of the formula [II]:

wherein Ro is a residue of a nitrogen-containing fused heterocycliccarboxylic acid having an absolute configuration of “R” which isobtained by removing hydroxy group from the carboxyl group of saidcarboxylic acid (in which the nitrogen atom contained in the residue isprotected), R¹ and R² are a lower alkyl group, and E is an esterresidue, obtained in claim 1 to a catalytic reduction to reduce thecyano group thereof and then subjecting to alkanoylation to give an Stype 2-substituted hydroxy-2-(6-substitutedanimomethylindolidinyl)butyric ester compound of the formula [V]:

wherein R³ is a lower alkanoyl group, and other symbols are as definedabove, subjecting the compound [V] to nitrosation reaction andrearrangement to give an S type 2-substituted hydroxy-2-(6-substitutedhydroxymethylindolidinyl)-butyric ester compound of the formula [VI]:

wherein the symbols are as defined above, subjecting the compound [VI]to an ester hydrolysis to give an S type2-hydroxy-2-(6-hydroxymethylindolidinyl)butyric acid compound of theformula [IX]:

wherein the symbols are as defined above, or a salt thereof, andsubjecting the compound [IX] to an intramolecular cyclization reaction,and thereafter or at the same time as the cyclization reactionconverting the acetal group thereof into a ketone group, and optionallyconverting the resultant product into a salt thereof.
 3. A process forpreparing a camptothecin compound of the formula [XVI]:

wherein the groups R⁵¹-R⁹¹ are each a hydrogen atom or an unprotectedsubstitutent, or a salt thereof, which comprises reacting the S type4-hydroxypyranoindolidine compound of the formula [VIII]:

or a salt thereof obtained in claim 2 with an o-acylaniline compound ofthe formula [XIV]:

wherein the groups R⁵-R⁹ are a hydrogen atom or a protected orunprotected substituent, to give a camptothecin compound of the formula[XVII]:

wherein the symbols are as defined above, and when the groups R⁵-R⁹ areprotected, subjecting the compound [XVII] to removal of the protectinggroup, and further optionally to conversion into a salt thereof.
 4. Anitrogen-containing fused heterocyclic carboxylic acid having anabsolute configuration of “R” of the formula [XIX]:

wherein Y is substituted or unsubstituted arylsulfonyl group or analkylsulfonyl group, and n is 0 or 1, or a salt thereof.
 5. The processaccording to claim 1 wherein R^(o) is a residue obtained by removing ahydroxy group from the carboxyl group of an R type nitrogen-containingfused heterocyclic carboxylic acid of the formula (XIX):

wherein Y is a substituted or unsubstituted arylsulfonyl group or analkylsulfonyl group, and n is 0 or
 1. 6. The process according to claim1 wherein R^(o) is a residue obtained by removing a hydroxy group fromthe carboxyl group of an R type nitrogen-containing fused heterocycliccarboxylic acid of the formula (XIX):

wherein Y is a substituted or unsubstituted arylsulfonyl group or analkylsulfonyl group, and n is 0 or 1.